ChemicalBook CAS DataBase List Baricitinib

Baricitinib synthesis

5synthesis methods

Product Name:Baricitinib
CAS Number:1187594-09-7
Molecular formula:C16H17N7O2S
Molecular Weight:371.42

Baricitinib, also known as INCB028050 or LY3009104, is a selective orally bioavailable JAK1/JAK2 inhibitor with nanomolar potency against JAK1 (5.9 nM) and JAK2 (5.7 nM). INCB028050 inhibits intracellular signaling of multiple proinflammatory cytokines including IL-6 and IL-23 at concentrations <50 nM. INCB028050 was also effective in multiple murine models of arthritis, with no evidence of suppression of humoral immunity or adverse hematologic effects. Baricitinib was approved for the treatment of rheumatoid arthritis (RA) in the United States. Synthetic Description Reference: Xu, Jiaojiao; Cai, Jin; Chen, Junding; Zong, Xi; Wu, Xuan; Ji, Min; Wang, Peng. An efficient synthesis of baricitinib. Journal of Chemical Research. Volume 40. Issue 4. Pages 205-208. Journal. (2016). Synthetic Description Reference: Anon. Crystalline forms in the preparation of 3-azetidineacetonitrile, 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]. IP.com Journal. Volume 19. Issue 5A. Pages 1-3. Journal; Patent. (2019). Synthetic Description Reference: Xu, Qiang; Wu, Siqing; Huang, Shuang; Li, Weisi; Tang, Jingyu; Yang, Jian. Preparation of Baricitinib. Assignee Jiangsu Zhongbang Pharmaceutical Co., Ltd., Peop. Rep. China. CN 108129482. (2018). Synthetic Description Reference: Zheng, Xuchun; Zhang, Yiping; Wu, Yihua. Process for synthesizing baricitinib compound as JAK inhibitor and intermediates. Assignee Hangzhou Cheminspire Technologies Co., Ltd., Peop. Rep. China. CN 106946917. (2017). Synthetic Description Reference: Zhang, Feng; Che, Xiaoming; Huang, Xiaojing; Zhu, Suhua; Xue, Yuquan. Process for preparation of Baricitinib. Assignee Nanjing Yoko Pharmaceutical Co., Ltd., Peop. Rep. China; Nanjing Yoko Biopharmaceutical Research Co., Ltd.; Nanjing Yoko Biopharmaceutical Group Co., Ltd. CN 107176955. (2017). Synthetic Description Reference: Simig, Gyula; Volk, Balazs; Katai Fadgyas, Katalin; Nagy, Tamas; Toth Lauritz, Maria; Sipos, Eva; Dancso, Andras; Szabo, Eva. Method and intermediate for the production of baricitinib. Assignee Egis Gyogyszergyar Zrt., Hung. WO 2017109524. (2017). Synthetic Description Reference: Zheng, Xuchun; Zhang, Yiping; Wu, Yihua. A process for preparing baricitinib and its intermediates. Assignee Hangzhou Cheminspire Technologies Co., Ltd., Peop. Rep. China. CN 106496195. (2017). Synthetic Description Reference: Kobierski, Michael Edward; Kopach, Michael E.; Martinelli, Joseph R.; Varie, David Lee; Wilson, Thomas Michael. Processes and intermediates for the preparation of {1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. Assignee Eli Lilly and Company, USA. WO 2016205487. (2016).

Synthetic Routes

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Reference: Xu, Jiaojiao; Cai, Jin; Chen, Junding; Zong, Xi; Wu, Xuan; Ji, Min; Wang, Peng. An efficient synthesis of baricitinib. Journal of Chemical Research. Volume 40. Issue 4. Pages 205-208. Journal. (2016).

1187594-13-3 Synthesis

2-(1-(ethylsulfonyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

1187594-13-3
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1187594-09-7
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Yield:1187594-09-7 83.8%

Reaction Conditions:

Stage #1:2-[1-ethanesulfonyl-3-[4-(7-[(2-(trimethylsilyl)ethoxy)methyl]-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl]acetonitrile with lithium tetrafluoroborate;water in acetonitrile at 75;
Stage #2: with ammonium hydroxide;water in acetonitrile; pH=9 - 10 at 0 - 10;Product distribution / selectivity;

Steps:

61.5
To a solution of 2-(1-(ethylsulfonyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (6, 327 g, 655 mmol) in acetonitrile (3 L) and water (300 mL) was added LiBF₄(614 g, 6.55 mol, 10.0 equiv). The resulting reaction mixture was stirred at 75° C. for overnight. The reaction mixture was cooled to 0° C. before a solution of ammonium hydroxide (NH₄OH, 570 mL) in water (2.2 L) was added slowly to keep the temperature below 10° C. (pH 9-10). The mixture was stirred at room temperature for overnight. When the reaction was deemed complete, water (10 L) was added and the resulting mixture was vigorously stirred for 3 h at room temperature. The solids were collected by filtration, washed with water (6.7 L) and heptane (6.7 L), and dried in vacuum oven at 45° C. over the weekend. The dried solid was then dissolved in 20% MeOH in dichloromethane (12 L), and was purified by column chromatography on 1.3 Kg of silica gel eluting with a 20% MeOH in dichloromethane solution (18L) to afford 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (7, 204 g, 243.3 g theoretical, 83.8% yield) as an off-white solid. For 7: ¹H NMR (300 MHz, d6-DMSO) δ 1.25 (t, 3H), 3.25 (q, 2H), 3.75 (s, 2H), 4.25 (d, 2H), 4.65 (d, 2H), 7.10 (d, 1H), 7.65 (dd, 1H), 8.50 (s, 1H), 8.70 (s, 1H), 8.95 (s, 1H), 12.2 (bs, 1H); MS: m/z calcd. 372.12; found: 372.0.

References:

INCYTE CORPORATION US2009/233903, 2009, A1 Location in patent:Page/Page column 58; 60